This is a transcript of the soundtrack from VPS Webinar 1, which is a video recording of a slide presentation. You can view the video accompanying the soundtrack on the VPS website at VPS Webinar of 16 January 2013: Vulvodynia research update – Dr David Nunns.

A list of the papers cited in this webinar is available at References for VPS Webinar of 16 January 2013: Vulvodynia research update – Dr David Nunns.

Approximate timings of the slides have been provided in order to aid quick location.

Slide 1 (00:00)    Introduction

Thank you for joining us! As I look outside the window at the moment, it’s minus four [degrees Celsius], and the garden’s full of snow, so for those of you in Australia – please enjoy the warmth, because we’re not feeling it here! Our study days that we’ve held have been in bad weather occasionally, so people really haven’t been able to travel, so this form of presentation I hope is going to improve information, but without the travel!

Slide 2 (01:10)    Clinical research and vulvodynia

Very specifically, I wanted to talk about research, and this is mentioned time and time again amongst women who come to the workshops: how does research that is carried out by health professionals get translated into clinical practice? This is a very important area for clinicians to appreciate because if we produce the research that produces the results, you as patients need to know how you can access that treatment and those results.

Very basically, clinical research is any form of gathering data, information and facts, so that we can advance our knowledge, and there’s many forms of data. In particular, in vulval pain, we see a large amount of qualitative data, data which has quite a large question base, and things are looked for rather than numerical results, whether a treatment works or not. So this is quite analytical: an example of qualitative research for vulvodynia might be the experience of women who’ve undergone treatment, or the partner’s experience of their partner experiencing vulval pain. Quantitative – usually you’re going to get numbers, it’s a specific question. It might be: does treatment A work over treatment B? Prospective versus retrospective data – again, this is important, because if we look back through hospital sets of notes to see if treatment X worked for vulvodynia, invariably we get gaps in our knowledge because the notes are incomplete or people can’t recall certain things. So, prospective data is much better: those studies are always going to be stronger.

Trial designs – well, there’s a real thumbs-up for systematic reviews and randomised controlled trials, which are going to be the best way of assessing whether treatment A is better than treatment B. Randomised controlled trials are where a treatment is randomised against usually a placebo, or another treatment, and the patient who’s eligible for the study has a coin tossed by the triallist and the patient’s randomly allocated to treatment A or B. That eliminates bias, and that generally gives us the best answer to the question and takes away any professional bias or any leaning towards an outcome. The weaker studies, case series and case reports – well, they’re really just small groups of patients with a condition who’ve had a treatment, and we can’t really generalise that treatment to everybody. So, just to bear in mind when you’re looking at the literature, and there is much on the internet, on research relating to vulvodynia.

Why is it important? It’s incredibly important, because all our clinical practice is based on good quality research, and if we have research, we have evidence, then this is incorporated into guidelines, endorsed by medical colleges and disseminated widely amongst clinicians. This is happening with vulvodynia and I’ll come on to that on the next slide. Potentially, we’ve got through Nice, which is the National Institute of Clinical Excellence, which is based in the UK, we’ve got the potential to influence national practice. If a guideline is endorsed by Nice generally, people wake up, particularly the commissioners or the buyers of services of hospitals – they will purchase services related to a condition if this is endorsed by this organisation, and they look at all the evidence available. So, without research, we have very little.

Slide 3 (05:11)    Guidelines for the management of vulvodynia (British Society for the Study of Vulval Disease, 2010)

Just to bring you up to date with what’s happening in the UK, this is a guideline for the management of vulvodynia. I was part of this group, and we were a mixture of doctors and a patient representative, Fabia Brackenbury. This was published and we looked at fifty high quality papers in the medical literature to support a series of guidance for general doctors working in women’s health, that’s GPs and hospital specialists. We tended to exclude small studies that weren’t particularly well controlled, or case reports, studies which really just had very little conclusion. Even then, when we look at vulvodynia, there’s still very little in terms of good quality research out there.

Slide 4 (06:14)    Guidelines for the management of vulvodynia: some salient points

I’ve just picked up a few random points from the guidance, and you might think this is incredibly straightforward.  For the first point: ‘An adequate pain history should be taken to assess the degree of symptoms and the impact on the woman’. I mean, you might think that’s pretty straightforward for a patient who’s got vulvodynia, that you take a pain history, but we know that many health professionals still treat vulval pain with Canesten or an antifungal – they think of the problem as a skin condition rather than a pain condition. So, that’s why that simple level of guidance is there. And that’s based on evidence, because vulvodynia is a pain condition.

‘A team approach may be necessary’ – absolutely! You do need a team approach for vulvodynia – you need to combine treatments, and a couple of other things I’ve mentioned there, techniques to desensitise the pelvic floor – they can be beneficial, and intralesional injections may be considered. Again, these are treatments based on evidence – somebody has gone to the effort of trialling these treatments and publishing them in the literature.

Slide 5 (07:38)    Review of vulvodynia treatment success rates in published studies

The problems with vulvodynia and research, however, are that you get incredible varieties in outcome, from medical, surgical and behavioural – behavioural would be psychological, psychosexual therapy interventions – and this is for a number of reasons. This might help explain why we simply haven’t answered the question: what is the best way of treating vulvodynia? Different doctors make different diagnoses, so a woman who presents with vulval pain may have different diagnoses made by different health professionals, and a woman with vulvodynia might get a different assessment by different doctors. So, inclusion criteria can vary. As a rule, we should distinguish between ‘provoked’ and ‘unprovoked’ pain for clinical trials, but the reality is many women have a combination of the two.

Follow-up rates vary. A treatment might give benefit at six weeks, but at six months, a year, it may have worn off, so really that’s a very short-term benefit of a treatment. It’s the long-term benefit that we’re really interested in.

Placebo I’ll come onto in a sec, but very important: does the treatment really work, or is there a placebo effect or would a dummy treatment be equally effective? And very important: outcome data. To this date, we still don’t have good quality outcomes. How does your doctor assess whether you’ve had a good outcome as a result of the treatments that he or she’s given you? Well, the doctor could ask you: are you the same, better, worse? Or you could fill a questionnaire in, a standardised questionnaire which is quite useful, because you can score a lot of your symptoms, and examination, that’s another way of assessment, where you’d use a Q-tip swab just to touch the vulval area and if it was painful before the treatment, and painless after the treatment on the Q-tip touch, then that would indicate that maybe that treatment worked. But we still don’t do this very well – really it’s probably a combination of outcomes we need to look at.

And then, treatments are empirically-based: we tend to just give treatments we think will work, as health professionals.

Here’s a quick picture of a simple visual analogue scale [referring to slide, which shows a scale using faces with happier/sadder expressions indicating different pain levels]. You get a score from the level of pain, and scores are helpful when it comes to research, because we can compare pre-and post-treatment.

Slide 6 (10:49)    Placebo response is important!

Placebo is very important. I’ll just talk about lignocaine gel. Lignocaine gel is very commonly used for vulval pain. It’s an anaesthetic ointment; it’s a numbing agent; it offers patients a fairly quick fix if they’ve got pain; it can be applied two to three times a day. It can sting for some patients, so you have to use it with caution initially. This original study showed that if you use lignocaine overnight for vestibulitis – what we used to call ‘vestibulitis’, it’s now ‘vestibulodynia’ – over seven weeks, 76% of patients would be able to have sex compared to 36% of patients before the treatment. That would be very encouraging as a treatment, and the lignocaine would smother a cotton wool ball, and that would be placed into the vagina nightly for seven weeks. This was a case series; there was no control arm.

We do have another study, however, that looks at the use of desipramine and lidocaine for vulvodynia – this is a randomised trial, a better-controlled trial, where patients were randomised to one of the four groups below. Desipramine is a drug for neuropathic pain. It’s taken by mouth. It’s  a bit like nortriptyline or amitriptyline. But the point is, those patients, when they had lidocaine cream and placebo compared to those patients who had placebo cream and placebo, there was a greater reduction in pain level for those patients having the placebo cream and the lidocaine cream, even though the patients with the lidocaine cream did improve. So, we just have to be careful when we come to treatments, that it may not be the treatment’s that’s working, and the dummy treatment may do as well, if not better, than the treatment. This is just a well recognised fact of research: placebo response is significant.

Slide 7 (13:24)    Skin changes in vulvodynia

I’m just going to focus a bit on pain, more on the science of pain. One of the questions we get asked at the VPS is about nerve endings and skin. The picture there [refers to slide] shows a variety of different pain/touch/hot/cold sensors in the skin, and we all have these as a normal part of skin function. In vulvodynia, we used to believe that there was an inflammation, or a redness or an angriness in the skin that gave pain, but now we don’t believe that, because when the skin from women with vulvodynia has been compared with control skin, there doesn’t seem to be any difference in the inflammation that’s there. So, it’s not an eczema or a virus or a precancerous change in the skin that’s causing the pain. We think there’s probably an increase in the local blood flow and the reasons for that aren’t clear. But there is evidence to show that perhaps there are more nerve endings in the skin, and an increase in the pain-producing chemicals produced at the tips of the nerves, so there’s the nociceptors there [indicates the nociceptors on the slide diagram], which detect pain. The chemicals calcitonin gene-regulatory peptide and Substance P, these are two chemicals produced at the tips of these nerves, and again, scientific research would suggest that in vulvodynia, these are increased.

Slide 8 (15:14)    Cross-section of normal skin

Skin: the reason why vulval disease becomes difficult, for many health professionals, is because skin is a surface, vulval skin is thinner, and there are lots of chemicals going on the surface of the skin. This is a simple biopsy cross-section of skin under the microscope. You’ve got a top epidermis, which is a protective layer, a dermis beneath it which is less protective, and within that are the blood vessels and the nerve endings. In this section of skin, you’ve got a whole variety of nerve endings which are beyond the naked eye and the light microscope networking through the skin.

Slide 9 (16:06)    Does recurrent vulvovaginal thrush develop into vulvodynia?

One of the questions that we often ask is: why vulvodynia? To finish off, I’m just going to talk about two bits of research that have been carried out in 2011/2012. Many women with vulvodynia report a history of recurrent thrush. Series after series, study after study shows that women with vulvodynia have had thrush treatment, or have had recurrent thrush in the past. It’s almost the norm that antifungal treatments have been used. We know that Candida is very common in the vagina. So the question is: does vulval thrush develop into vulvodynia? There’s an important message there, because recurrent thrush is incredibly common in the population.

Slide 10 (16:53)    Does recurrent vulvovaginal thrush develop into vulvodynia? Discussion of 2011 study modelling vulvodynia in mice

It’s hard to prove this in humans, so this one study in 2011 aimed to recreate a thrush model in the laboratory using mice. This was a series of experiments using mice, where thrush was induced in the mice and then they were treated with an antifungal soon after. There was a series of experiments, and the mice had thrush introduced into their vulvas, and onto their hind leg as a  control, and there was another control group who had saline. This was basically laboratory-induced thrush in animals and this was repeated attacks, and this was a sustained attack of thrush on the mice. They then assessed the skin to see if there was an excess of nerve fibres.

So, how do you assess vulvodynia in mice? Well, vulvodynia exhibits a phenomenon called ‘allodynia’, where when the skin is touched, there is an excess of pain rather than touch, so this is called allodynia and this is the perception of pain when there is touch. This is a problem of nerve endings rather than the skin – this is the central processes going wrong in the brain, a memory of pain. The brain is integral in the perception of pain, and it is integral in the sensory feeling of pain when the skin is touched. In this experiment, the vulvas of the mice were touched and the hindpaws were touched with what’s called a von Frey fibre, which is like a small hair, and when the hair bends, the pressure can be measured. If there’s pain, usually there’s a recoil response to the tip of the hair.

Slide 11 (19:34)    Does recurrent vulvovaginal thrush develop into vulvodynia? (Results)

So what were the results? Well, there was a series of experiments, but what they found was when the mice were given three consecutive doses of Candida with antifungal, so they had three attacks of thrush, they noticed that 40% of the mice had allodynia. With the first two attacks of thrush and treatment, the thrush was treated and the symptoms settled, the mice were not touch-sensitive, they weren’t allodynic after two attacks, but after three attacks, when the infection was cleared up, they still remained hypersensitive to touch. Another experiment showed that if it was a single prolonged attack of Candida and the mouse wasn’t treated for many days with antifungal, this led in a significant proportion of the mice to touch sensitivity in 86% of the group even after the infection was cleared up.

Zymosan is a chemical a bit like Candida, it’s a part of the wall of the fungus, so it’s similar to Candida. Zymosan was also given to the mice, and a lot of the mice experienced allodynia when it was given repeatedly, but the response was very variable. One mouse out of the 19 had touch sensitivity right the way through the entire experiment, but many had allodynia only after four or five weeks.

Slide 12 (21:51)    Does recurrent vulvovaginal thrush develop into vulvodynia? (Diagrams)

In conclusion, the research is showing that you can produce an allodynia or a touch-sensitive response with recurrent thrush. They looked at nerve endings, and this slide, if you go from left to right [indicates on slide], this is basically the picture that you get when you stain nerve endings – this is different to the previous picture, but you can see the epithelium there and PGP is the stain they used. This is the control group, the mice with saline and fluconazole, which is the antifungal, Candida and fluconazole without allodynia, without touch sensitivity, and this third picture is Candida and fluconazole with allodynia. This is from their paper, and it shows that when the mice were allodynic or they had touch sensitivity, there was an increase in the nerve fibres as demonstrated on this picture, and they counted these.

Slide 13 (22:51)    Does recurrent vulvovaginal thrush develop into vulvodynia? (Conclusion)

I think the message is that we feel that there is something in the fact that recurrent bouts of thrush may develop into vulvodynia, and that this recurrent infection can produce a neuropathic pain syndrome. We need to push really for early diagnosis of recurrent thrush, and early treatment, before a pain pathway sets up. However, it doesn’t explain other things like herpes – herpes is a very nasty inflammatory condition of the vulva – and we don’t know what the nerves were doing before the mice were treated. But I thought it was encouraging to see such a research study done because it lends much more evidence to vulvodynia having a physical or organic reason for pain developing. I know there’s a huge psychological/psychosexual aspect to the problem, but it’s not purely psychological/psychosexual – I think this sort of research gives us a bit more of an understanding into perhaps reasons why nerve endings develop. The genetic link is interesting in that we think there may be a ‘pain gene’, and so certain individuals are more likely to develop pain than others and this may be relevant to vulvodynia.

Slide 14 (24:34)    Do enoxaparin injections help in the treatment of localised provoked vulvodynia?

Moving on to a treatment: this paper was produced only last year in one of the medical journals. For it to be published in a medical journal, it has to be peer-reviewed by a variety of reviewers and then submitted, so it’s subject to some scrutiny. The question was: do enoxaparin injections help in the treatment of localised provoked vulvodynia, touch sensitivity, the allodynia problem that you get in localised provoked vulvodynia, or vestibulodynia – so, painful sex, pain during tampons etc, that would be that group of women. Enoxaparin is a standard treatment that we use in hospitals all the time, and we use it to prevent blood clots in the leg and in the chest. We give it as a self-administered injection into the fat, not the vulva. The group that did this research had done a lot of work showing that in women, not animals, women, the nerve endings in vestibular skin are increased in number and there is an increased number of mast cells, shown in the picture, and heparinase activity. Heparinase is essentially an enzyme – it’s a dissolver, it weakens the cell wall, allows nerve growth, and mast cells are protectors of infection in the skin, and they’re important for allergy and anaphylaxis, so these are important cells in the skin. We know that enoxaparin, which is the injection, blocks the heparinase, that’s the dissolver, the enzyme we call it, that protects the mast cells. If heparinase acts on the mast cell, and weakens it, there may be an increase in nerve endings in the skin – this was the hypothesis that they were working on. A presence of heparinase in the skin weakens the heparin sulphate, which is the protector of the cell, to weaken the mast cell, and the nerve growth.

Slide 15 (26:56)    Do enoxaparin injections help in the treatment of localised provoked vulvodynia? (continued)

So, a randomised controlled trial – 40 women with the symptoms randomised to one of two groups. One was placebo and the other was the treatment arm. It was one injection a day of Clexane, or enoxaparin, for 90 days, and the other control group had saline for 90 days. Unfortunately, for this part of the trial, you need the biopsy before and after, and if we drill down into the figures, this is a hospital team that have a big interest in vulval disease, of the 224 women that were suitable for the treatments, we were getting only 40 randomised, because many women weren’t happy with the biopsy.

Slide 16 (27:49)    Do enoxaparin injections help in the treatment of localised provoked vulvodynia? (Results)

What were the results? Well, you can see that from this table [indicates slide], along the bottom, it says ‘End of treatment’ and further along, ‘End of research’. The black is placebo and the grey is the actual treatment. We can see that there were greater responses in the patients treated with enoxaparin than placebo, so 75% of the women, i.e. 13 out of 20 women had more than a 20% reduction in pain level compared to the placebo group. But again, look at the placebo group: out of 18 patients in the placebo group, five of the patients, 27%, had more than a 20% reduction in sensitivity, so the placebo group here is significant.

Slide 17 (28:53)    Do enoxaparin injections help in the treatment of localised provoked vulvodynia? (continued)

So, the data is promising. Seven treatment patients and three placebo patients had painless sex at the end of the study, and these women also had biopsies before and after, and if they improved with the treatment, they had a reduction in the number of nerve endings in the skin after treatment. These are women who’ve had two biopsies; they improved with the Clexane injections; they had a reduction in the number of nerve endings in the skin.

Slide 18 (29:32)    Do enoxaparin injections help in the treatment of localised provoked vulvodynia? (Conclusion)

So, does it work? Can you take this away as a possible treatment? Well, we answer one research question with another, and they certainly didn’t suggest that this was for everybody, because of bruising, expense, administration of the injections for 90 days. There was a big improvement with the placebo group, but possibly there is a subgroup of patients with vestibulodynia who may benefit from this, but it’s ‘watch this space’. But it’s research like this, ‘from small acorns grow trees’: we hope that this sort of research progresses and develops, and it’s only through asking questions like this based on science, that we will get the answers.

Slide 19 (30:25)    NHS Choices page: Clinical trials and medical research

This is a trial website that the NHS has, the National Health Service, which has a lot on research. There’s not a huge amount on vulval disease, but nationally, it’s the site we would go to where we would look for clinical trials – NHS Choices.

Slide 20 (30:46)    Summary

I’m going to finish there. All I’d say is that I think we still have lots of questions to answer, and it’s not all high science: research can be about pathways of care which are still unclear, and research will decide whether a pathway is good or not. I’ve chosen those subjects because this is the first webinar, but clearly if you have a research question that you want answering that’s more physical treatment-based, then we’re happy to do a future webinar. The last thing is to mention the online research projects that are on our site, because there are a number of qualitative studies looking at women with vulvodynia and partners of women with vulvodynia that you can do online, so all the information we can get, the better.